Compositions and methods to evaluate hepatobiliary/gastrointestinal health, enterohepatic circulation, and drug interactions

Abstract

The present invention relates to the synthesis and use of a novel trifluorinated bile acid analog, that being, CA-sar-TFMA which is useful as an imaging probe, diagnostic agent or contrast agent and is resistant to bacterial deconjugation, wherein the trifluorinated bile acid analog can be used as a 19F MRI tracer exhibiting an increased half-life due to its resistance to choloylglycine hydrolase.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]The present application claims priority to U.S. Provisional Patent Application No. 61 / 901,819 filed on Nov. 8, 2013, the contents of which are herein incorporated by reference herein for all purposes.STATEMENT OF FEDERAL SUPPORT[0002]This invention was made with government support under Grant No. FD-U-004320 awarded by the Food and Drug Administration, and Grant Nos. DK067872 and DK093406 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Field of the Invention[0004]The present invention relates to detection probes and methods of use, and more particularly, related to 19F-labeled bile acid tracer and methods of use to evaluate hepatobiliary and / or gastrointestinal health, enterohepatic circulation, and / or drug interactions.[0005]Description of the Related Art[0006]Bile acids are produced in the liver as end products of cholesterol metabolism. After their synthes...

AI Technical Summary

Benefits of technology

The present invention provides a novel trifluorinated bile acid analogue that can be used as an imaging probe for magnetic resonance imaging (MRI) and is resistant to bacterial deconjugation. This compound can be administered to patients and used to diagnose and treat bile acid-related disorders. The use of this compound as an MRI probe can help to better understand the mechanisms underlying bile acid malabsorption and evaluate the function of anti-BAM drugs. The invention also provides a kit for administering the compound to different body tissues to monitor movement of bile acids.

Problems solved by technology

This dysregulation leads to hepatic overproduction of bile acids, exceeding the ileal absorptive capacity, thereby increasing colonic exposure and diarrhea.

In the United States, diagnosis of BAM is limited by the lack of sensitive, specific and cost-effective tests.

However, these methods are time-consuming, difficult, not readily available, or not validated clinically.

Hence, BAM is often diagnosed by administering bile acid sequestrants, such as colesevelam, in a therapeutic trial13,14, an approach that is not FDA-approved for this indication, lacks specificity and has a high rate of false-negative diagnosis.7

However, when CA-lys-TFA was used an imaging agent, it was susceptible to bacterial metabolism, that being, removal of its amino acid side chain by choloylglycine hydrolase (CGH), a bacterial bile acid deconjugating enzyme located predominantly in the colon and in smaller amounts in the terminal ileum.15

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